Stereo view of a channel consisting of the transmembrane pore of the MthK channel docked with the cytoplasmic pore of mGIRK1. The front subunit of the tetramer has been removed to provide a clearer view of the pore structure. The coloured spheres indicate positions where mutations affect ion conduction or blocking by impermeant cations. Reproduced, with permission, from Nishida & MacKinnon © 2003 Elsevier Science.

It is easy to envisage ion channels simply as holes in the cell membrane through which ions can pass freely in both directions, and this is indeed the case for many channels. However, there is a subset of K+ channels that conduct ions more efficiently into than out of the cell. These are known as inward rectifier K+ (IRK) channels. A new study published in Cell identifies the unique structural features of these channels that account for this property.

IRK channels are important for restoring the resting potential of neurons after electrical activity. During an action potential, Na+ ions flow into the neuron, and if all the K+ channels were open, K+ ions would be expelled, thereby dissipating the positive charge that is generated inside the neuron. To stop this from happening, the IRK channels become blocked by intracellular cations, such as polyamines, which can bind inside the channel but cannot pass through. As the action potential subsides, the neuron transiently becomes hyperpolarized, and the IRK channels re-open to allow K+ ions to enter and restore the cell to its resting potential.

What are the structural properties of the IRK channels that cause them to function as rectifiers? It was suspected that part of the answer lay in the carboxyl terminus, because mutations in this region affected the binding affinity of blockers. Nishida and MacKinnon examined the crystal structure of the amino and carboxyl termini of mGIRK1, a G-protein-gated IRK channel from the mouse. Both termini lie inside the cell, and the authors found that they assemble into a tetramer to form a pore-like structure that extends the total length of the channel to nearly 60Å. The pore is lined with negatively charged amino acid side chains, which provide an excellent binding substrate for polyamines.

The efficacy of blocking by polyamines is higher at positive membrane potentials. So, blocking is more efficient when the membrane is depolarized. Early measurements implied that the voltage dependence of the blocking reaction is greater than would be predicted from the charge of the blocker alone, and the elongated shape of the mGIRK1 channel provides an explanation for this observation. The length of the channel allows it to accommodate extra K+ ions that are expelled outwards when the blockers bind, and this additional charge displacement accounts for the increased voltage dependence of channel block.

Nishida and MacKinnon have shown that structural analysis can provide fascinating insights into the phenomenon of rectification, and it has also enabled them to identify new targets for mutational studies of the IRK channels.